A typical transdermal drug delivery patch comprises a flexible backing on which are applied, either as one layer or in spatial separation: a pressure sensitive adhesive, the desired pharmaceutically active drug, and cutaneous penetration enhancers. The cutaneous penetration enhancers are chemicals that enhance the permeation of the drug compounds into the skin to achieve the desired delivery rate. Chemical enhancers useful in transdermal drug delivery applications are well documented and fall into the categories of alcohols, fatty acid esters, fatty acids, amides, sulfoxides, polyols and surfactants. Such enhancers preferably have molecular weights in the range of 20 to 20,000.
Acrylic adhesives are well suited for transdermal drug delivery applications because they can be synthesized with inherent pressure-sensitive properties, and are conformable and adherable to human skin under a range of conditions for an extended period of time. However, when they are compounded with enhancers commonly used in transdermal patches, they may lose their pressure sensitive adhesive properties, such as tack, peel adhesion, and shear adhesion, due to either plasticization of the adhesive by the enhancers or migration of the enhancers through the adhesive to the patch surface. The plasticization by enhancers results in loss of cohesive strength and is evidenced by a large decrease in shear adhesion. The migration of enhancers to the adhesive-skin bond interface causes the transdermal patches to lose tack and peel adhesion. Although controlled migration/release of enhancers is desired to help drug permeation into the skin, a fast, uncontrolled migration of enhancers to the bond interface results in phase separation between the enhancer and the adhesive and is not desired.
"Migration of enhancers" as used in the present application refers to the fast, uncontrolled migration to the bond interface, which is disadvantageous and undesirable in drug delivery applications. "Resistant to migration of enhancers" means the adhesive has the ability to resist the undesired migration of enhancers. "Tolerant" means resistant to plasticization by chemical enhancers such that the adhesive, when compounded with the chemical enhancers, maintains its adhesive properties.
Therefore, the desired acrylic adhesive for transdermal drug delivery applications should be tolerant to plasticization by chemical enhancers so that adhesive integrity can be maintained, and resistant to migration of enhancers so that the pressure sensitive tackiness and adhesion can be maintained.
Several approaches have been taken in attempts to make adhesives more enhancer tolerant. One such method, disclosed in U.S. Pat. No. 5,573,778, has been to graft polystyrene onto an acrylic adhesive. This approach, however, has a number of disadvantages, which include incompatibility with many types of enhancers and drugs and the loss of adhesive properties over time when the enhancers are depleted from the system due to diffusion into the skin.
Another approach, described in European Patent Application 455458, has been to post-cure the adhesive with an electron beam which reportedly causes the adhesive to be tolerant of alcohol-based enhancers used in transdermal drug delivery devices. However, this reference does not disclose if this method works for other classes of enhancers, i.e. fatty acid esters, glycol esters, or amides.
U.S. Pat. Nos. 4,822,676 and 3,558,574 disclose the inclusion of t-octyl acrylamide and diacetone acrylamide, respectively, in pressure sensitive adhesive acrylic copolymer compositions. These references do not disclose the use of these compositions with cutaneous penetration enhancers.
Attempts have also been made to reduce the loss of adhesive integrity by increasing the level of crosslinking in the adhesive. Although crosslinking does increase the cohesive strength, the adhesive often loses its tack and peel adhesion, and thus does not adhere well to the skin.
Accordingly, it is the objective of the present invention to provide a pressure sensitive adhesive which possesses the ability to tolerate enhancer plasticization and to resist uncontrolled enhancer migration.